The present invention relates to hydrogels which have a good controlled release behaviour, and to processes to prepare such hydrogels.
The fast developments in the field of molecular biology and biotechnology have made it possible to produce a large number of pharmaceutically interesting products in large quantities. For instance, pharmaceutically active peptides and proteins can suitably be used as drugs in the treatment of life-threatening diseases, e.g. cancer, and of several types of viral, bacterial and parasital diseases; in the treatment of e.g. diabetes; in vaccines, e.g. for prophylactic aims, and for anticonception purposes. Especially the specialized biological activities of these types of drugs provide tremendous advantages over other types of pharmaceutics.
To illustrate the fast developments, it has been reported (see e.g. Soeterboek and Verheggen, Pharm. Weekblad 130 (1995) 670-675) that in the United States of America, about 275 biotechnological products are in phase IV studies, while more than 500 products are under investigation.
Examples of (recombinant) proteins, which are considered very interesting from a pharmacological point of view, are cytokines, such as interleukines, interferons, tumor necrosis factor (TNF), insulin, proteins for use in vaccines, and growth hormones.
Due to their nature, proteins and proteinaceous products, including peptides, which group of products will be referred to as protein drugs herein-below, cannot be administered orally. These products tend to degrade rapidly in the gastrointestinal tract, in particular because of the acidic environment and the presence of proteolytic enzymes therein.
Moreover, to a high extent protein drugs are not able to pass endothelial and epithelial barriers, due to their size and, generally, polar character.
For these reasons, protein drugs have to be brought in the system parenterally, i.e. by injection. The pharmacokinetical profile of these products is, however, such that injection of the product per se requires a frequent administration. For, it is a known fact that proteinaceous material is eliminated from the blood circulation within minutes.
In other words, since protein drugs are chemically and/or physically unstable and generally have a short half-time in the human or animal body, multiple daily injections or continuous infusions are required for the protein drug to have a desired therapeutic effect. It will be evident that this is inconvenient for patients requiring these protein drugs. Furthermore, this type of application often requires hospitabilization and has logistic drawbacks.
In addition, it appears that at least for certain classes of pharmaceutical proteins, such as cytokines which are presently used in e.g. cancer treatments, the therapeutic efficacy is strongly dependent on effective delivery, e.g. intra- or peritumoral. In such cases, the protein drugs should be directed to the sites where their activity is needed during a prolonged period of time.
Hence, there is a need for delivery systems which have the capacity for controlled release. In the art, delivery systems consisting of polymeric networks in which the proteins are loaded and from which they are gradually released have been proposed.
More in detail, at present, two major types of polymeric delivery systems can be distinguished: biodegradable polymers and non-biodegradable hydrogels.
Biodegradable polymers, e.g. polylactic acid (PLA) and copolymers of PLA with glycolic acid (PLGA), are frequently used as delivery systems for proteins.
Proteins can be incorporated in pharmaceutical delivery systems, e.g. microspheres, by a variety of processes. In vitro and in vivo, usually a biphasic release profile is observed: an initial burst followed by a more gradual release. The burst is caused by proteinaceous material present at or near the surface of the microspheres and by proteinaceous material present in pores. The gradual release is ascribed to a combination of diffusion of the proteinaceous material through the matrix and degradation of the matrix. Especially for larger proteins diffusion in these matrices is negligible, so that the release depends on the degradation of the polymer. The degradation can be influenced by the (co)polymer composition. A well-known strategy to increase the degradation rate of PLA is co-polymerization with glycolic acid.
Although delivery systems based on biodegradable polymers are interesting, it is very difficult to control the release of the incorporated protein. This hampers the applicability of these systems, especially for proteins with a narrow therapeutic window, such as cytokines and hormones. Furthermore, organic solvents have to be used for the encapsulation of the protein in these polymeric systems. Exposure of proteins to organic solvents generally leads to denaturation, which will affect the biological activity of the protein. Furthermore, the very stringent requirements of registration authorities with respect to possible traces of harmful substances may prohibit the use of such formulations of therapeutic drugs in human patients.
Also hydrogels are frequently used as delivery systems for proteins and peptides. Hydrogels can be obtained by crosslinking a water-soluble polymer yielding a three-dimensional network which can contain large amounts of water. Proteins can be loaded into the gel by adding the protein to the polymer before the crosslinking reaction is carried out or by soaking a preformed hydrogel in a protein solution. So, no (aggressive) organic solvents have to be used to load the hydrogels with protein molecules.
In contrast with the biodegradable polymers, the release of proteins from hydrogels can be easily controlled and manipulated by varying the hydrogel characteristics, such as the water content and the crosslink density of the gel. However, a major disadvantage of the currently used hydrogel delivery systems is that they are not biodegradable. This necessitates surgical removal of the gel from the patient after the release of the protein in order to prevent complications of inclusion of the empty hydrogel material (wound tissue is frequently formed).
Biodegradable hydrogels have been used in the preparation of delivery systems for protein drugs. One of these systems comprises crosslinked dextrans obtained by coupling glycidyl methacrylate (GMA) to dextran, followed by radical polymerization of an aqueous solution of GMA-derivatized dextran (dex-GMA). In this respect, reference is made to Van Dijk-Wolthuis et al. in Macromolecules 28, (1995), 6317-6322 and to De Smedt et al. in Macromolecules 28, (1995) 5082-5088.
Proteins can be encapsulated in the hydrogels by adding proteins to a solution of GMA-derivatized dextran prior to the crosslinking reaction. It appeared that the release of the proteins out of these hydrogels depends on and can be controlled by the degree of crosslinking and the water content of the gel (Hennink et al., J. Contr. Rel. 39, (1996), 47-57).
Although the described crosslinked dextran hydrogels were expected to be biodegradable, these hydrogels are rather stable under physiological conditions. This can is further elaborated in Example 5. It is shown among other that the dissolution time of dextran hydrogels obtained by polymerization of dextran derivatized with glycidyl methacrylate (DS=4) had a dissolution time of about 100 days. Dextran hydrogels, wherein the dextrans have a higher degree of substitution, did not show any signs of degradation during 70 days, even at extreme conditions.
The object of the present invention is to provide a slow or controlled release delivery system which does not possess the above-mentioned disadvantages, and especially does not require the use of organic solvents, does not show the undesired and uncontrollable burst effects, and do not possess a poorly controllable release behaviour. The present invention aims to combine the advantages of both types of known delivery systems, viz. a system, (bio)degradable under physiological conditionsxe2x80x94either chemically and/or enzymaticallyxe2x80x94, with controlled protein drug release.
The present invention provides safe and easily controllable delivery systems, based on particular biodegradable hydrogels, which increase the applicability of protein drugs for the treatment of various diseases. The risks associated with these drugs, such as bursts in the release profile, and the inconvenience for the patient are reduced, while the therapeutic efficacy of drug treatments using the hydrogels of the present invention is increased.
More in detail, the present invention relates to a biodegradable hydrogel comprising bonds which are hydrolysable under physiological conditions. The hydrogels of the present invention contain hydrolytically labile spacers, which spacers are broken in human or animal bodies. As roughly indicated herein-above, a hydrogel is defined as a water-swollen, three-dimensional network of crosslinked hydrophilic macromolecules. More in detail, the hydrogels of the invention consist of two interpenetrating networks interconnected to one another through hydrolysable spacers. Hydrogels generally contain from 20 to more than 99 wt. % water.
Further, the invention relates to a method for the preparation of a hydrogen, wherein macromolecules, e.g. polymers, which contain bonds which are hydrolysable under physiological conditions, are crosslinked in an aqueous solution.